Acetic Acid → HCID 178467571, compound

HRID 914018Notes

Reaction equation

HRID 914018 reaction equation
[Cl:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1.C([BH3-])#N.[Na+].C=O.C(O)(=O)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:10]2[C:5](=[C:6]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 178467576HCID 178467576, compound

Product 1

HCID 178467571HCID 178467571, compound

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Procedure

(±)-tert-Butyl 4-((1-(3,5-dichloro-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (120 mg, 0.23 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (2 mL), cooled to 0° C., and treated with sodium cyanoborohydride (72 mg, 1.15 mmol) and formalin (0.84 mL). After 5 min, the reaction was treated with a drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by preparative HPLC to afford 30 mg (30%) as a clear oil. 1H-NMR (CD3OD, 500 MHz) δ 7.53 (d, J=1.8 Hz, 1H), 7.33-7.45 (m, 2H), 6.99-7.14 (m, 3H), 4.66 (q, J=6.7 Hz, 1H), 3.41-3.52 (m, 2H), 3.38 (qAB, JAB=9.2 Hz, 2H), 2.81-2.90 (m, 2H), 2.77(s, 3H), 2.61-2.69(m, 2H), 2.07-2.18 (m, 2H), 1.48 (m, 3H). Mass spec.: 442.44 (MH)+.

Workup

  1. concentrationThe reaction was concentrated
  2. customflushed with several volumes of methanol which
  3. washThe crude secondary amine was eluted in 2 M ammonia in methanol
  4. concentrationconcentrated
  5. dissolutionThe resulting residue was dissolved in acetonitrile (2 mL)
  6. temperaturecooled to 0° C.
  7. waitAfter 5 min
  8. customThe ice bath was removed
  9. stirringstirring
  10. waitcontinued for 1 h
  11. concentrationThe reaction was concentrated
  12. custompurified by preparative HPLC
  13. customto afford 30 mg (30%) as a clear oil

Sources & evidence

ORD record
ord-eebd85efccad4f33bf85dffdb23f2b6c
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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